Bacterial and plant toxins utilize unique mechanisms of affecting cytotoxicity not currently used in the standard practice of medical oncology . Definition of the mechanisms of action of these agents in vitro will facilitate their rational introduction to the clinic. Prior studies by the principal investigator had demonstrated that cholera toxin could inhibit increases in intracellular calcium in response to [Tyr4]-bombesin in small cell lung carcinoma (SCLC) cell lines. We have extended these studies by examining the effect of cholera toxin on the growth of lung carcinoma cell lines. Nine of 12 SCLC cell lines and four of 14 non-SCLC cell lines were sensitive to growth inhibition by CT. To define the mechanism by which growth inhibition occurs, we examined the expression of the ganglioside GM1, the receptor for CT. Sensitive SCLC cell lines all had notable expression of GM1, whereas resistant cell lines had reduced or absent GM1 expression. In contrast, while non-SCLC cell lines sensitive to CT all had easily detectable GM1, resistant non-SCLC in 70% of cases had detectable GM1 expression. Thus, the mechanism for resistance to CT in non-SCLC cannot be related to absence of cell surface receptor. Cholera toxin causes an increase in cyclic AMP (CAMP) after activation of G8, the stimulatory G protein of adenylate cyclase. No difference in the capacity to generate CAMP in the presence of an inhibitor of CAMP degradation exists in CT-sensitive compared to CT-insensitive non-SCLC. These studies therefore underscore the value of defining the mechanism of CT-mediated growth inhibition in lung carcinoma cells, as the mechanism can be related neither to possessing a receptor for CT nor to the increase in CAMP evoked by the agent. Clinical trials utilizing a bacterial toxin targeted via IL2 (the diphtheria-toxin-IL2 fusion protein DAB486IL2) and a ricin-derived immunotoxin (IgG-RFB4-SMPT-dga) have been developed to explore the clinical usefulness of macromolecular cytotoxins in cutaneous T-cell lymphoma and relapsed CD22 positive B cell lymphoma, respectively. Pharmacodynamic evaluation of toxin effect in the targeted cell population will be a major focus of these studies, in addition to clinical response.